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Reliable assessment of telomere maintenance mechanisms in neuroblastoma

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Item Type:Article
Title:Reliable assessment of telomere maintenance mechanisms in neuroblastoma
Creators Name:Meeser, A. and Bartenhagen, C. and Werr, L. and Hellmann, A.M. and Kahlert, Y. and Hemstedt, N. and Nürnberg, P. and Altmüller, J. and Ackermann, S. and Hero, B. and Simon, T. and Peifer, M. and Fischer, M. and Rosswog, C.
Abstract:BACKGROUND: Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. METHODS: Whole genome sequencing (WGS) data of 68 primary neuroblastoma samples were analyzed. Telomere length was calculated from WGS data or by telomere restriction fragment analysis (n = 39). ALT was assessed by C-circle assay (CCA, n = 67) and detection of ALT-associated PML nuclear bodies (APB) by combined fluorescence in situ hybridization and immunofluorescence staining (n = 68). RNA sequencing was performed (n = 64) to determine expression of TERT and telomeric long non-coding RNA (TERRA). Telomerase activity was examined by telomerase repeat amplification protocol (TRAP, n = 15). RESULTS: Tumors were considered as telomerase-positive if they harbored a TERT rearrangement, MYCN amplification or high TERT expression (45.6%, 31/68), and ALT-positive if they were positive for APB and CCA (19.1%, 13/68). If all these markers were absent, tumors were considered TMM-negative (25.0%, 17/68). According to these criteria, the majority of samples were classified unambiguously (89.7%, 61/68). Assessment of additional ALT-associated parameters clarified the TMM status of the remaining seven cases with high likelihood: ALT-positive tumors had higher TERRA expression, longer telomeres, more telomere insertions, a characteristic pattern of telomere variant repeats, and were associated with ATRX mutations. CONCLUSIONS: We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.
Keywords:Neuroblastoma, Telomere Maintenance, Alternative Lengthening of Telomeres, Telomerase
Source:Cell and Bioscience
ISSN:2045-3701
Publisher:BioMed Central
Volume:12
Number:1
Page Range:160
Date:24 September 2022
Official Publication:https://doi.org/10.1186/s13578-022-00896-2
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/21715/Preprint version

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